A5042796405- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Viral Infectious Diseases and Gene Expression in Insects
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Pancreatic and Hepatic Oncology Research
- Cancer Genomics and Diagnostics
- Biosimilars and Bioanalytical Methods
- T-cell and B-cell Immunology
- BRCA gene mutations in cancer
- Monoclonal and Polyclonal Antibodies Research
- PARP inhibition in cancer therapy
- DNA Repair Mechanisms
- vaccines and immunoinformatics approaches
- Virus-based gene therapy research
- Nanoplatforms for cancer theranostics
- AI in cancer detection
- Cytokine Signaling Pathways and Interactions
- Mathematical Biology Tumor Growth
- Cell Image Analysis Techniques
- Inflammatory mediators and NSAID effects
- Cancer Research and Treatments
- Cancer, Stress, Anesthesia, and Immune Response
- Prostate Cancer Treatment and Research
- Radiomics and Machine Learning in Medical Imaging
University of Pennsylvania
2016-2025
Hospital of the University of Pennsylvania
2020-2025
Parker Institute for Cancer Immunotherapy
2018-2023
Stanford University
2022
Cancer Research Institute of the Slovak Academy of Sciences
2009-2019
UPMC Hillman Cancer Center
2013-2018
Cancer Research Institute
2009-2018
Abramson Cancer Center
2013
CD25 monoclonal antibody therapy rapidly and durably depletes T regs in cancer patients through a mechanism consistent with reprogramming.
Abstract Purpose: Immunotherapy has the potential to improve dismal prognosis in pancreatic ductal adenocarcinoma (PDA), but clinical trials, including those with single-agent PD-1 or PD-L1 inhibition, have been disappointing. Our aim was examine immune landscape of PDA as it relates aspects tumor biology, neoepitope burden. Experimental Design: We used publicly available expression data from 134 primary resection samples The Cancer Genome Atlas stratify patients according a cytolytic T-cell...
Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of cell stemness, poor expansion capacity, and exhaustion during prolonged tumor exposure are major causes CAR therapeutic resistance. Single-cell RNA-sequencing analysis from a first-in-human trial metastatic prostate cancer identified two independently validated states associated with antitumor potency or lack efficacy. Low expression PRDM1 , encoding the BLIMP1 transcription...
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has achieved tremendous success treating B malignancies; however, some patients fail to respond due poor autologous fitness. To improve response rates, we investigated whether disruption of the co-inhibitory receptors CTLA4 or PD-1 could restore CART function. CRISPR-Cas9-mediated deletion in preclinical models leukemia and myeloma improved CAR proliferation anti-tumor efficacy. Importantly, this effect was specific not seen upon...
In carcinogen-driven cancers, a high mutational burden results in neoepitopes that can be recognized immunologically. Such carcinogen-induced tumors may evade this immune response through “immunoediting,” whereby adapt to pressure and escape T cell–mediated killing. Many lack neoepitope burden, it remains unclear whether immunoediting occurs such cases. Here, we evaluated cell immunity an autochthonous mouse model of pancreatic cancer found low absence predicted derived from tumor mutations,...
Resistance to immunotherapy is one of the biggest problems current oncotherapeutics. WhileT cell abundance essential for tumor responsiveness immunotherapy, factors that define T inflamed microenvironment are not fully understood. We conducted an unbiased approach identify tumor-intrinsic mechanisms shaping immune microenvironment(TME), focusing on pancreatic adenocarcinoma because it refractory and excludes cells from TME. From human tumors, we identified EPHA2 as a candidate intrinsic...
Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T-cell therapy. Mechanisms driving immunosuppression poor infiltration PDA are incompletely understood. Here, we use genetically engineered mouse models of that recapitulate hallmarks human to demonstrate CD40 pathway activation is required for response radiotherapy ICB αCTLA-4 αPD-1. The...
Abstract The immune system exerts antitumor activity via T cell–dependent recognition of tumor-specific antigens. Although the number tumor neopeptides—peptides derived from somatic mutations—often correlates with and survival, most classically defined high-affinity neopeptides (CDNs) are not immunogenic, only rare CDNs have been linked to rejection. Thus, rules antigen remain incompletely understood. Here, we analyzed neopeptides, activity, clinical outcome 6,324 patients across 27 types....
Breast cancers with BRCA1/2 alterations have a relatively high mutational load, suggesting that immune checkpoint blockade may be potential treatment option. However, the degree of cell infiltration varies widely, and molecular features contributing to this variability remain unknown.We hypothesized genomic signatures might predict immunogenicity in breast cancers. Using The Cancer Genome Atlas (TCGA) data, we compared (89) without (770) either germline or somatic alterations. We also...
Abstract Chimeric antigen receptor (CAR) T cell therapy has shown promise in treating hematologic cancers, but resistance is common and efficacy limited solid tumors. We found that CAR cells autonomously propagate epigenetically programmed type I interferon signaling through chronic stimulation, which hampers antitumor function. EGR2 transcriptional regulator knockout not only blocks this interferon–mediated inhibitory program also independently expands early memory with improved against...
Adeno-associated virus (AAV)-mediated gene therapy is currently being pursued as a treatment for the monogenic disorder α-1-antitrypsin (AAT) deficiency. Results from phase I and II studies have shown relatively stable dose-dependent increases in transgene-derived wild-type AAT after local intramuscular vector administration. In this report we describe appearance of transgene-specific T-cell responses two subjects that were part trial. The patient with more robust response, which was...
Antigen-specific T cells traffic to, are influenced by, and create unique cellular microenvironments. Here we characterize these microenvironments over time with multiplexed imaging in a melanoma model of adoptive cell therapy human patients treated checkpoint inhibitor therapy. Multicellular neighborhood analysis reveals dynamic immune infiltration inflamed tumor neighborhoods associated CD8
We developed a deep learning Pathomics image analysis workflow to generate spatial Tumor-TIL maps visualize and quantify the abundance distribution of tumor infiltrating lymphocytes (TILs) in colon cancer. Colon cancer lymphocyte detection hematoxylin eosin (H&E) stained whole slide images (WSIs) has revealed complex immuno-oncologic interactions that form TIL-rich TIL-poor habitats, which are unique each patient sample. compute Tumor%, total lymphocyte%, TILs% as proportion microenvironment...
Multiplexed imaging technologies provide insights into complex tissue architectures. However, challenges arise due to software fragmentation with cumbersome data handoffs, inefficiencies in processing large images (8 40 gigabytes per image), and limited spatial analysis capabilities. To efficiently analyze multiplexed data, we developed SPACEc, a scalable end-to-end Python solution, that handles image extraction, cell segmentation, preprocessing incorporates machine-learning-enabled,...
Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity. In this study, we assessed safety, feasibility, and preliminary efficacy huCART19-IL18 in with relapsed or refractory lymphoma after previous therapy. Using a 3-day manufacturing process, administered...
BACKGROUNDNeoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes is poorly understood. Here, we explore immunogenicity and properties 4 receptors (TCRs) specific for KRASG12V restricted to HLA-A3 superfamily class I alleles.METHODSA phase 1 clinical vaccine trial targeting was conducted. TCRs HLA-A*03:01 or HLA-A*11:01 were isolated vaccinated patients healthy individuals. A comprehensive analysis TCR...